This competitive renewal application for a K24 Mid-Career Investigator Award in Patient-Oriented Research is to provide continued support for the development of Dr. John E. Nestler as a clinical investigator and, most importantly, as a research mentor. Dr. Nestler is Professor of Medicine at Virginia Commonwealth University's Medical College of Virginia, and has been a productive patient-oriented investigator whose research focus has been the pathophysiologic role of insulin resistance in the polycystic ovary syndrome (PCOS), a disorder that affects 6-10% of women of childbearing age. Dr. Nestler has an established track record of mentorship of young clinical investigators, and has been highly successful in providing research training to young investigators during the 4 year tenure of the active K24 grant. The broad long-term objective of Dr. Nestler's studies has been to conduct both mechanistic and translational studies exploring the role of insulin resistance in PCOS. The specific studies proposed in this application, which are currently funded by an NIH R01 grant, are designed to determine: 1) if decreasing circulating insulin directly by inhibition of islet insulin release with diazoxide in obese women with PCOS (i) decreases renal clearance of D-chiro-inositol (uCIDCI) and (ii) increases the circulating concentration of DCI; 2) if decreasing circulating insulin indirectly, by improving insulin sensitivity with pioglitazone, in obese women with PCOS (i) decreases uCIDCI, (ii) increases the circulating concentration of DCI, and (iii) enhances the insulin-stimulated release of the putative DCI-inositolphosphoglycan mediator during an OGTT [oral glucose tolerance test]; and 3) if acutely increasing circulating insulin in non obese women with PCOS increases uCIDCI and/or the metabolic clearance rate of DCI. These studies will be conducted on the General Clinical Research Center (GCRC) using state of the art methodologies, such as the modified minimal model FSIVGTT [frequently-sampled intravenous insulin tolerance] to determine insulin sensitivity. The K24 renewal will allow Dr. Nestler to continue his increased mentorship of young investigators and to enhance his personal growth as a clinical investigator. It will do so by continuing to provide Dr. Nestler with increased protected time and to maintain decreases in administrative duties and clinical service responsibilities. As a result of the K24 renewal, Dr. Nestler will be able to devote 75-85% effort to research, personal development in clinical research, and, most importantly, the training and mentorship of young investigators. [unreadable] [unreadable] [unreadable]